EP3044229B1 - Peptides for use in the treatment of oral mucositis - Google Patents

Peptides for use in the treatment of oral mucositis Download PDF

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EP3044229B1
EP3044229B1 EP14844276.7A EP14844276A EP3044229B1 EP 3044229 B1 EP3044229 B1 EP 3044229B1 EP 14844276 A EP14844276 A EP 14844276A EP 3044229 B1 EP3044229 B1 EP 3044229B1
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seq
rivpa
peptide
radiation
mucositis
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EP3044229A1 (en
EP3044229A4 (en
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Oreola Donini
Annett Rozek
Jackson Lee
John North
Michael Abrams
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Soligenix Inc
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Soligenix Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the innate immune response is an evolutionarily conserved protective system associated with the barriers between tissues and the external environment, such as the skin, the orogastric mucosa and the airways. Providing rapid recognition and eradication of invading pathogens as well as a response to cellular damage, it is often associated with inflammatory responses and is a key contributor to the activation of adaptive immunity. Innate defenses are triggered by the binding of pathogen and/or damage associated molecules (PAMPs or DAMPs) to pattern-recognition receptors, including Toll-like receptors (TLRs).
  • PAMPs or DAMPs pathogen and/or damage associated molecules
  • TLRs Toll-like receptors
  • Pattern recognition receptors are found in and on many cell types, distributed throughout the body in both circulating and tissue resident compartments, and serve to provide early "danger" signals that lead to the release of non-specific antimicrobial molecules, cytokines, chemokines, and host defense proteins and peptides as well as the recruitment of immune cells (neutrophils, macrophages, monocytes) in a highly orchestrated fashion (Janeway 2002; Beutler 2003; Beutler 2004; Athman 2004; Tosi 2005; Doyle 2006; Foster 2007; Matzinger 2002). Moreover the innate immune system is directly involved in the generation of tolerance to commensal microbiota in the gastrointestinal tract and in gastrointestinal repair and immune defense (Santaolalla, 2011; Molloy 2012).
  • Mucositis is the clinical term for damage done to the mucosa by anticancer therapies. It can occur in any mucosal region, but is most commonly associated with the mouth, followed by the small intestine. Though many mucositis scales are used clinically, the two most commonly used grading systems are the NCI and WHO scales.
  • Mucositis affects 500,000 people in the US per year and occurs in 40% of patients receiving chemotherapy (Sonis 2010, Curr. Op.). Mucositis almost always occurs in patients with head and neck cancer treated with radiation therapy (>80% incidence of severe mucositis) (Elting et al. 2008).
  • Mucositis is common (40-100% incidence) in patients undergoing high dose chemotherapy and stem cell transplantation (SCT) where the incidence and severity of mucositis depends greatly on the nature of the conditioning regimen used for myeloablation (Murphy 2007).
  • SCT stem cell transplantation
  • 5-FU and irinotecan are particularly noted for causing mucositis but it also occurs with newer agents such as mTOR inhibitors and kinase inhibitors (Mateus et al. 2009; Sankhala et al. 2009). Mucositis can be seriously debilitating and can lead to infection, sepsis, the need for parenteral nutrition and narcotic analgesia.
  • the intestinal damage causes severe diarrhea.
  • Mucositis occurs 3-12 weeks after the initiation of radiation, or 3-12 days after the initiation of chemotherapy, and resolves after 2-3 weeks, assuming no further chemotherapy or radiation treatment is undertaken.
  • RIVPA (SEQ ID NO. 5) is an IDR (Innate Defense Regulator), a new class of short, synthetic peptides with a novel mechanism. Designed to mimic one of the recently discovered functions of natural mucosal defense peptides, IDRs have no direct antibiotic activity but modulate host responses, increasing survival after infections with a broad range of bacterial Gram-negative and Gram-positive pathogens, as well as accelerating resolution of tissue damage following exposure to a variety of agents including bacterial pathogens, trauma and chemo- or radiation-therapy.
  • IDR Innate Defense Regulator
  • RIVPA SEQ ID NO. 5
  • other IDR peptides Since the drug would be given soon after the chemotherapy infusion or radiation, the IV dosage form of RIVPA (SEQ ID NO. 5) is well suited to the mucositis indication.
  • Preclinical efficacy results obtained with RIVPA (SEQ ID NO. 5) in mouse and hamster models of mucositis indicate that dosing every third day should be able to cover the mucositis "window" with seven to fourteen doses, depending on the duration of chemotherapy or radiation exposure.
  • ARS Acute radiation syndrome
  • Radiation induces dose-proportional injury to mammalian cells and tissues.
  • the injury may be limited to point mutations in somatic and/or germ-line DNA that may be associated with long-term effects such as an increased risk of cancer or birth defects.
  • radiation induces chromosomal abnormalities such as breaks and translocations, which again increases the risk of cancers and birth defects, and if severe enough will result in the death of rapidly dividing cells within hours of exposure.
  • radiation can denature proteins, resulting in almost immediate death of cells and tissues.
  • the tissues with rapidly dividing cells that are the most commonly affected by moderate doses of radiation include the bone marrow, the gastrointestinal tract and the testis.
  • Exposure to radiation is associated with acute effects, including skin rashes and burns, bone marrow failure, including anemia, depressed white blood cell counts, and thrombocytopenia, as well as gastrointestinal toxicity such as diarrhea, and more chronic effects such as the development of tumors, especially sarcomas and leukemias, and birth defects.
  • the first symptoms of ARS typically are nausea, vomiting, and diarrhea. These symptoms will start within minutes to days after the exposure, will last for minutes up to several days, and may come and go. Then the person usually looks and feels healthy for a short time, after which he or she will become sick again with loss of appetite, fatigue, fever, nausea, vomiting, diarrhea, and possibly even seizures and coma. This seriously ill stage may last from a few hours up to several months.
  • GI-ARS gastrointestinal acute radiation syndrome
  • GI-ARS consists of diarrhea, dehydration, enterobacterial infection, and in severe cases, septic shock and death (Potten 1990).
  • GI-ARS is thought to be caused by direct damage to stem cells within the base of the crypts of Lieberkuhn, resulting in mitotic cessation and death through apoptotic mechanisms (Potten 1997a, Potten 1997b).
  • the integrity of gastrointestinal mucosa depends on a rapid proliferation of a pool of pluripotent stem cells at the bottom of the crypts (Brittan 2002, Gordon 1994, Potten 1997b).
  • stem cell death is thought to be the critical element in this process, since surviving intestinal stem cells appear to be sufficient for reconstitution of a crypt-villus unit (Potten 1990). Renewal of the intestinal epithelial barrier depends upon an active stem cell compartment similar to the hematopoietic system. Intestinal crypt-villus precursor clonogen cells are particularly sensitive to ionizing radiation exposure such that with increasing radiation dose, crypt-villus clonogen cells cannot produce enough cells to repopulate the villi. This results in blunting and diminution in villus height and eventual functional incapacity, leading to decreased nutrient absorption and barrier function, loss of fluid and electrolytes, and bacterial translocation through the intestinal barrier (Monti 2005, Zhao 2009).
  • the intestinal stem cell compartment is not the only compartment sensitive to ionizing radiation.
  • Another critical factor involving the response of the GI tract to a major physical insult is hypoperfusion of the intestine.
  • Persistent gut hypoperfusion is an important inciting event in the development of the systemic inflammatory response syndrome and multi-organ failure (MOF) (Moore 1999).
  • Increased intestinal vascular permeability together with capillary leakage has been observed in the early period after irradiation (Cockerham 1984; Eddy 1968, Willoughby 1960).
  • Additional post-irradiation alterations include moderate dilatation and tortuosity of small arterial vessels, reduction in numbers and/or lengths of vessels followed by later occurring hemorrhagic patterns (Eddy 1968).
  • hematopoietic growth factors i.e., granulocyte- and/or granulocyte-macrophage colony stimulation factors (G-CSF and G/M-CSF) and erythropoietin (EPO), and hematopoietic stem cell/bone marrow transplantation
  • G-CSF and G/M-CSF granulocyte- and/or granulocyte-macrophage colony stimulation factors
  • EPO erythropoietin
  • the cause of death within 15 days of radiation exposure is usually damage to the GI tract whereas after 15 days death usually is a consequence of bone marrow injury.
  • the recovery process may last from several weeks up to 2 years (CDC 2013).
  • RIVPA SEQ ID NO. 5
  • Microbial cells are distinct from cells of animals and plants that are unable to live alone in nature, existing only as parts of multicellular organisms. Microbial cells can be pathogenic or non-pathogenic, depending, in part, on the microorganism and the status of the host. For example, in an immunocompromised host, a normally harmless bacterium can become a pathogen. Entry into host cells is critical for the survival of bacterial pathogens that replicate in an intracellular milieu. For organisms that replicate at extracellular sites, significance of bacterial entry into host cells is less well defined.
  • Drug resistance remains an obstacle in the ongoing effort to fight infection.
  • penicillin was effective in treating Staphylococcus aureus until the bacterium became resistant.
  • new antibiotics such as vancomycin and methicillin, were developed; these successfully cured S. aureus infection.
  • methicillin-resistant strain of S. aureus evolved in the 1970s, and have been plaguing hospitals worldwide ever since. More recently, vancomycin-resistant strains of S. aureus have surfaced.
  • IDRs Innate Defense Regulators
  • IDRs Innate Defense Regulators
  • WO 2008/040111 A1 and US 2013/224231 A1 which relate to peptides for use in treating and preventing immune-related disorders including treating and preventing infection by modulating innate immunity, disclose in one aspect compositions and uses thereof for modulating innate immunity, and in another aspect peptides and uses thereof effective in reducing dipeptidyle peptidase (DPPIV) activity.
  • DPPIV dipeptidyle peptidase
  • WO 03/072061 A2 relates to pharmaceutical preparations and methods for treating and alleviating gastrointestinal toxicity and dysfunction resulting from intensive cytoablative therapies.
  • the methods and compositions provide prophylaxis and therapy of the gastrointestinal complications induced by chemotherapy and radiotherapy including diarrhea, mucositis (e.g. oral and esophageal), stomatitis and proctitis.
  • peptide wherein the peptide is a peptide comprising the amino acid sequence of any of SEQ ID NOs: 5, 10, 24, 27, 28, 31, 34, 63, and 90, or a pharmaceutical salt, ester or amide thereof and a pharmaceutically-acceptable carrier, diluent or excipient.
  • the peptide is preferably SEQ ID NO: 5 or a pharmaceutical salt, ester, or amide thereof and a pharmaceutically-acceptable carrier, diluent, or excipient.
  • the peptide may be administered orally, parenterally, transdermally, intranasally.
  • the effective amount of peptide administered to a subject is at least 1.5 mg/kg. In a preferred embodiment the effect amount of peptide administered to a subject is about 1.5 mg/kg to 6 mg/kg.
  • the peptide may be administered to the subject every third day during radiation or chemotherapeutic agent administration.
  • the peptide may be administered in combination with an oral dosage form of a topically active corticosteroid or a metabolite thereof to the subject, wherein the oral dosage form is effective for topical or local treatment of the gastrointestinal tract and oral cavity of the subject and further wherein the subject exhibits symptoms of inflammation due to tissue damage arising from radiation or chemotherapy treatment.
  • topically active corticosteroids include, but are not limited to, beclomethasone 17,21-dipropionate, alclomethasone dipropionate, budesonide, 22S budesonide, 22R budesonide, beclomethasone-17-monopropionate, clobetasol propionate, diflorasone diacetate, flunisolide, flurandrenolide, fluticasone propionate, halobetasol propionate, halcinocide, mometasone furoate, and triamcinolone acetonide.
  • the topically active corticosteroid is beclomethasone diproprionate.
  • topically active corticosteroid in each dosage form may vary from patient to patient, and may be readily determined by one skilled in the art by well-known does-response studies. Such effective amounts will generally range between about 0.1 mg/day to about 8 mg/day, and more typically range from about 2 mg/day to about 4 mg/day.
  • the dosage form of RIVPA (SEQ ID NO. 5) is an aqueous, aseptically processed, sterile solution for injection. Each vial contains 5 mL of a 60 mg/mL solution (300 mg of RIVPA (SEQ ID NO. 5)). RIVPA (SEQ ID NO. 5) is formulated in Water for Injection and pH adjusted to a target value of 6.0. The formulation contains no excipients and has an osmolality of ⁇ 300 mOsm/kg.
  • RIVPA (SEQ ID NO. 5) drug product will be diluted in sterile saline to the appropriate concentration for injection, determined on a mg/kg basis by the recipient's weight and the designated dose level. Diluted RIVPA (SEQ ID NO. 5) will be administered as an intravenous (IV) infusion in 25 mL over 4 minutes, once every third day.
  • the peptides in Table 1 were synthesized using a solid phase peptide synthesis technique.
  • the resin was de-protected by adding 25% piperidine in DMF (30 ml) to the resin and mixing for 20 minutes.
  • the first coupling was made by mixing the 3mMol amino acid solution with 4mMol 2-(1H-benzitriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and 8mMol N,N-diisopropylethylamine (DIEPA).
  • HBTU 4mMol 2-(1H-benzitriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • DIEPA 8mMol N,N-diisopropylethylamine
  • the peptide was cleaved from the resin with the use of a cleavage cocktail containing 97.5 % Trifluoroacetic acid (TFA) and 2.5% water.
  • TFA Trifluoroacetic acid
  • the resin was allowed to swim in the cleavage cocktail for 1 1 ⁇ 2 hours.
  • the solution was then filtered by gravity using a Buchner funnel and the filtrate was collected in a 50 ml centrifugation tube.
  • the peptide was isolated by precipitating with chilled diethyl ether. After centrifuging and decanting diethyl ether the crude peptide was washed with diethyl ether once more before being dried in a vacuum desiccator for 2 hours.
  • the peptide was then dissolved in de-ionized water (10 ml), frozen at - 80°C and lyophilized. The dry peptide was then ready for HPLC purification.
  • Peptide +RIVPAx contains one N-methyl amino acid. This coupling was carried out by combining the N-methyl amino acid, PyBroP and N-hydroxybenzotriazole ⁇ H2O (HOBt) and DIEPA solutions together in the RV containing the resin. After allowing to couple for 45 minutes the N-methyl amino acid was then doubled coupled to ensure complete coupling. It was observed that the coupling following the N-methyl amino acid was not fully complete. Therefore this coupling was performed using N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) instead of HBTU. This still resulted in a crude peptide that typically contained two impurities totaling 30-40% of the total purity. The peptide was purified under modified HPLC conditions to isolate the pure peptide peak away from the closely eluting impurities.
  • H2O N-hydroxybenzotriazole ⁇ H2O
  • these peptides can also be synthesized with solution phase peptide synthesis techniques (Tsuda et al. 2010) and commonly known to experts in the art.
  • RIVPA SEQ ID NO. 5
  • IDRs modulate the innate defense response to tissue injury, reducing the severity of damage caused by the inflammatory cascade and enhancing resolution of disease. This attribute of IDRs has been demonstrated in chemotherapy-induced oral and GI mucositis in mice, in radiation-induced oral mucositis in hamsters and in DSS-induced colitis in mice. In each of these models, the initial damage is thought to trigger a cascade of innate defense signaling which increases the severity of the injury (Marks 2011; Sonis 2010). RIVPA (SEQ ID NO. 5) and other IDRs offset the signaling cascade, reducing the resultant severity of the injury and reducing the duration of severe tissue damage.
  • RIVPA (SEQ ID NO. 5) significantly reduced the severity and duration of mucositis in a model of radiation-induced oral mucositis in hamsters, particularly when administered every third day during the fractionated radiation therapy.
  • RIVPA SEQ ID NO. 5
  • cannulated male Golden Syrian hamsters were treated with 7.5 Gy of radiation, directed at the everted left cheek pouch, on Days 0, 1, 2, 3, 6, 7, 8 and 9.
  • Mucositis was evaluated every second day between Days 7 and 35, with peak mucositis severity generally occurring around Day 19.
  • RIVPA (SEQ ID NO. 5) significantly reduced the severity and duration of mucositis in a model of radiation-induced oral mucositis in hamsters, particularly when administered every third day during the fractionated radiation therapy.
  • RIVPA (SEQ ID NO. 5) (25 mg/kg IV) was administered either every third day starting on Day 0 and continuing until Day 33 (Q3d d0-33), or on days of radiation therapy (Days 0, 1, 2, 3, 4, 7, 8, 9) or every third day starting on Day 6 and continuing to Day 24 (Q3d d6-24).
  • RIVPA (SEQ ID NO. 5) was given 2 hours after radiation.
  • Figure 1 The results of this study are shown in Figure 1 .
  • RIVPA (SEQ ID NO. 5) treatment was most effective when administered every third day throughout the period or on days of radiation, whereas treatment starting 6 days after initiation of radiation was not beneficial (i.e., Q3d d6-24).
  • RIVPA (SEQ ID NO. 5) has also shown efficacy in mouse models of chemotherapy-induced oral and gastrointestinal mucositis, consistent with the response of the innate immune response to chemotherapy and / or radiation damage.
  • RIVPA (SEQ ID NO. 5) administration was associated with a statistically significant reduction in the duration of severe oral mucositis in a model of chemotherapy-induced mucositis in the mouse.
  • a trend towards reduced colitis was also observed, although the mild GI damage in the control group rendered the result not statistically significant.
  • 5-fluorouracil 60 mg/kg IP was administered to male C3H/HeN mice on Days -4 and -2.
  • RIVPA SEQ ID NO. 5
  • other IDRs modulate the innate defense response to tissue injury, reducing the severity of damage caused by the inflammatory cascade and enhancing resolution of disease.
  • IDRs can mitigate the response to radiation damage in an oral mucositis model ( Figure 1, Figure 2 ).
  • RIVPA SEQ ID NO. 5
  • IDRs are also able to reduce the duration and / or severity of gastrointestintal mucositis in a chemotherapy-induced mucositis model ( Figure 4 , Figure 5 , Figure 6 ).
  • RIVPA reduces bacterial burden and improves survival in the presence or absence of antibiotic treatment in various murine infection models, with consistent efficacy at dose levels of 25 mg/kg IV and higher and with an enduring pharmacodynamic effect of up to 5 days.
  • RIVPA (SEQ ID NO. 5) efficacy is complementary to antibiotic treatment in both normal and immune compromised mice. Efficacy of RIVPA (SEQ ID NO. 5) has been demonstrated against disease caused by Gram-positive (S. aureus and MRSA) and Gram-negative (Klebsiella, E. coli and B. pseudomallei ) infections.
  • RIVPA (SEQ ID NO. 5) has been tested both in combination with vancomycin treatment and as a stand-alone treatment.
  • RIVPA (SEQ ID NO. 5) treatment increased survival in a MRSA peritoneal infection model when administered in combination with a sub-optimal antibiotic dose of vancomycin (Study #: D-7-E-11).
  • Vancomycin treatment (3 mg/kg) was administered subcutaneously (SC), 1 and 5 h after infection. Survival was monitored once daily for 5 days. The results of this study are shown in Figure 7 .
  • RIVPA (SEQ ID NO. 5) is also effective when administered by itself.
  • Multiple studies with IV administered RIVPA (SEQ ID NO. 5) were conducted in a MRSA bacteremia model.
  • RIVPA (SEQ ID NO. 5) administration demonstrated a dose response in this model in either immunocompetent Balb/c mice or nu/nu mice lacking T-cells, with a single dose of 50 mg/kg resulting in statistically significant enhanced survival over the saline control.
  • MRSA USA300, 7.3log10 cfu
  • MRSA (USA300, 7.3log10 cfu) was administered via IV injection into the tail vein of female Balb/c mice at time 0.
  • RIVPA SEQ ID NO. 5
  • RIVPA SEQ ID NO. 5
  • RIVPA can be administered up to 24 h after the initiation of infection in the MRSA bacteremia model and still confer a survival benefit (data not shown). Hence its action is rapid.
  • a single dose of RIVPA SEQ ID NO. 5
  • RIVPA SEQ ID NO. 5
  • PK pharmacokinetic
  • the survival benefit conferred by RIVPA (SEQ ID NO. 5) treatment can be sustained for at least 21 days ( Figure 9 ).
  • RIVPA Local administration of RIVPA (SEQ ID NO. 5) has also been demonstrated to be effective when the administration is local to the site of infection.
  • RIVPA SEQ ID NO. 5
  • S. aureus Catalog No. 25923, ATCC, 6 ⁇ 10 7 cfu
  • RIVPA also significantly reduced bacterial load in neutropenic mice in an S. aureus thigh abscess infection model when administered as a local intramuscular (IM) injection.
  • RIVPA (SEQ ID NO. 5) 50 mg/kg was administered IM 24 h prior to infection and vancomycin (100 mg/kg) was administered SC at 1, 6 and 18 h after infection.
  • the number of bacterial cfu present in the infected thigh was assessed 24 h after initiation of infection in each group. The results of this study are shown in Figure 12 .
  • RIVPA SEQ ID NO. 5
  • IP locally
  • IV systemically
  • RIVPA RIVPA
  • a survival endpoint is shown for animals receiving the higher inoculum of bacteria (panel A). All animals receiving the lower inoculum survived in all groups (panel B) and were assessed for clinical signs (e.g., piloerection, decreased movement, hunched abdomen, etc.) 24 h after infection; these are summarized as clinical scores.
  • RIVPA Systemically administered RIVPA (SEQ ID NO. 5) is also efficacious in the case of skin injury and infection, accelerating skin healing in an MRSA skin infection model. Infection was initiated 1 day after the hair was removed from the dorsal area of each mouse.
  • RIVPA SEQ ID NO. 5
  • RIVPA SEQ ID NO. 5
  • Oral linezolid was used as the comparator and was administered daily at 12.5 mg/kg.
  • Non-GLP pilot toxicology studies indicated that the maximum tolerated dose (MTD) of a single administration of RIVPA (SEQ ID NO. 5), administered as an IV injection over 30 to 60 seconds, is 88 mg/kg (actual dose) in mouse.
  • MTD maximum tolerated dose
  • NBP nonhuman primates
  • RIVPA RIVPA
  • SEQ ID NO. 5 The safety of multiple daily injections of RIVPA (SEQ ID NO. 5) has also been evaluated in GLP studies in mice and cynomolgus monkeys.
  • doses of 20, 60, or 90 mg/kg/day were given IV for 14 days. Deaths were observed at the high dose, preceded mainly by labored respiration and recumbancy. Lethality was also observed in 1 animal given 60 mg/kg but no other animals exhibited clinical signs at this dose. No test article-related mortality or clinical signs were observed at 20 mg/kg. In survivors of all groups, there was no evidence of toxicity in any organ or abnormal biochemistry or hematology. No adverse effects were observed at 20 mg/kg for 14 days.
  • RIVPA (SEQ ID NO. 5) at 20, 80, 160 mg/kg/day was given IV to cynomolgus monkeys for 14 days. Transient decreased activity and partially closed eyes continued to be observed during and shortly after dosing at 160 mg/kg for the first 3 days in most animals, then sporadically throughout the remaining dosing period. In all cases, these clinical signs resolved within a few minutes. No adverse effects were observed on any other measured parameter or microscopically in any tissue. The administration of RIVPA (SEQ ID NO. 5) at doses of 20 and 80 mg/kg/day did not result in any evidence of toxicity. A dose level of 80 mg/kg/day was considered to be the No-Observed-Adverse-Effect-Level (NOAEL) for this study.
  • NOAEL No-Observed-Adverse-Effect-Level
  • RIVPA central nervous system
  • RIVPA SEQ ID NO. 5
  • RIVPA SEQ ID NO. 5
  • the administration of RIVPA was associated with transient, severe clinical signs such as drooping eye lids, tremor, prostration, paleness, convulsion and collapse.
  • the high dose caused a marked reduction in respiratory rate followed by bradycardia, hypotension and death.
  • NOAEL is considered to be 80 mg/kg/day for cynomolgus monkeys since transient clinical signs were limited to a single study and occurred in only 2 instances of the 98 administrations of the drug at this dose level.
  • RIVPA SEQ ID NO. 5
  • RIVPA SEQ ID NO. 5
  • the effect of RIVPA (SEQ ID NO. 5) on the innate defense system is highly selective. Consistent with these findings, no changes were observed in immune-related organ weights, histopathology, hematology and clinical chemistry during mouse and NHP 14-day toxicity studies. In the latter study, no effect on T-cell, B-cell or NK-cell counts was observed after 14 days of intravenous RIVPA (SEQ ID NO. 5) dosing in the NHP. RIVPA (SEQ ID NO. 5) did not promote the proliferation of either mouse or human normal blood cells in vitro, nor of primary human leukemia cells in vitro. Collectively, there is no indication of a potential for RIVPA (SEQ ID NO. 5) to cause immunotoxicity or non-specific immune activation. No hyperactivation or suppression of adaptive immune responses, or other impact on the phenotypes of cells associated with adaptive immunity, has been detected following RIVPA (SEQ ID NO. 5) administration.
  • the major toxicological finding was an acute-onset respiratory depression, accompanied by labored breathing, recumbency and transient decreased activity. At its most severe, the acute toxicity resulted in death. Clinical signs were all reversible when dosing was discontinued and animals were observed to recover within minutes, with no subsequent adverse sequellae of clinical symptoms or toxicological findings.
  • a cardiovascular/pulmonary safety pharmacology study in nonhuman primates confirmed no cardiac toxicity or QT prolongation was occurring.
  • RIVPA did not alter the recovery of circulating blood cell populations after the induction of leukopenia in CD-1 mice.
  • Leukopenia was induced with 2 IP injections of Cp (150 mg/kg on Day 1 and 100 mg/kg on Day 4), resulting in well-established leukopenia by Day 4 that persisted until approximately Day 10.
  • Saline or RIVPA (SEQ ID NO. 5) (20 or 50 mg/kg) was administered IV on Days 5, 7, 9 and 11.
  • Six animals per group were sacrificed on each of Days 6, 8, 10, 12 and 14 and evaluated for complete blood count and differential. Neither the levels nor dynamics of the total leukocyte and differential white blood cell counts were altered during the course of recovery when compared to the vehicle control group ( Figure 15 ).
  • RIVPA SEQ ID NO. 5
  • CYP450 enzymes the primary metabolism of RIVPA (SEQ ID NO. 5) by proteases throughout body tissues and the very minor role played by urine, feces and bile excretion in RIVPA (SEQ ID NO. 5) clearance suggests that pharmacokinetic drug-drug interactions will be minimal.
  • RIVPA Clinical experience with RIVPA (SEQ ID NO. 5) was obtained in a Phase 1 Study.
  • the primary objective of the study was to determine the maximum tolerated dose (MTD) of single and repeat ascending doses of RIVPA (SEQ ID NO. 5) injectable solution following IV administration in healthy volunteers.
  • the secondary objectives of this study included the assessment of the dose limiting toxicity (DLT), safety, PK and pharmacodynamic (PD) profiles of RIVPA (SEQ ID NO. 5) after single and repeated ascending IV doses of RIVPA (SEQ ID NO. 5).
  • the study was divided into 2 phases: a single-ascending dose (SAD) phase and a multiple-ascending dose (MAD) phase.
  • SAD single-ascending dose
  • MAD multiple-ascending dose
  • RIVPA Single IV doses of RIVPA (SEQ ID NO. 5) were well tolerated up to the maximum tested (8 mg/kg) and daily IV doses were well tolerated up to the maximum tested (6.5 mg/kg for 7 days). There were no dose limiting toxicities (DLTs) and the MTD was not reached in either phase of the trial. There were no deaths and no clinically significant, severe, or serious Adverse Events (AEs) reported during the study. No safety concerns or significant differences in mean values or changes from baseline were observed for vital sign measurements, clinical laboratory or electrocardiogram (ECG) results between drug-treated and placebo control subjects.
  • DLTs dose limiting toxicities
  • AEs Adverse Events
  • TEAEs The incidence of TEAEs for those subjects who received RIVPA (SEQ ID NO. 5) was not dose-related and events did not occur at a clinically significant higher rate for subjects who received RIVPA (SEQ ID NO. 5) compared to those who received placebo.
  • the most frequently reported TEAEs observed in more than one subject who received RIVPA (SEQ ID NO. 5) and in a higher proportion (%) than placebo subjects) were study treatment procedure-related events (General Disorders and Administration Site Conditions) such as vessel puncture site haematoma, vessel puncture site reaction and vessel puncture site pain. All vessel puncture-related events were mild and determined to be unrelated to study treatment by the QI.
  • TEAEs Nervous System Disorders, specifically headache and dizziness; these events were only mild to moderate. All other TEAEs were reported by only 1 subject at any given dose level (maximum of 3 dose levels). No clinically significant trends in the nature or duration of TEAEs were demonstrated for any study cohort.
  • TEAEs The highest incidence of TEAEs was observed at the 2 highest dose levels (4.5 and 6.5 mg/kg/day). The incidence of "possibly-related" events was also higher in the 2 highest dose levels. However, due to the small sample sizes (4 subjects received active treatment in each cohort), it was not possible to conclude whether the results definitely represented a dose-response. The majority of the TEAEs were not related to study treatment and were mild in severity with only one event reported as moderate. The most frequently reported TEAEs for subjects who received RIVPA (SEQ ID NO. 5) were General Disorders and Administration Site Conditions (i.e., procedure-related events) such as vessel puncture site haematoma, vessel puncture site reaction, and vessel puncture site pain.
  • Site Conditions i.e., procedure-related events
  • ALT alanine aminotransferase
  • RIVPA SEQ ID NO. 5
  • RIVPA SEQ ID NO. 5
  • Cmax maximum concentration
  • Tmax mean time of maximum concentration
  • RIVPA SEQ ID NO. 5
  • LLOQ lower limit of quantitation
  • Mucositis has been linked to the dysregulation of the innate defense system, resulting in a cascade of inflammatory action which further damages the mucosal lining and leads to overt mucositis (Sonis, 2004).
  • the chemotherapy or radiation treatment causes damage to the underlying endothelium and epithelium
  • the response of the innate defense system to the resulting "DAMPS” results in an inflammatory cascade which exacerbates this damage.
  • Recent studies evaluating gene expression in animals and humans pre-disposed to intense oral mucositis have supported the role of the innate defense system in the disease (Sonis, 2010).
  • lower gastrointestinal tract mucositis has also been attributed to similar mechanisms (Bowen, 2008).
  • Acute radiation exposure is associated with damage to the epithelium (skin), bone marrow (hematopoietic syndrome) and gastrointestinal tract (GI). Moreover, mortality becomes increasingly acute as the radiation exposure increases, limiting the potential for therapeutic intervention. Early mortality ( ⁇ 2 weeks) after acute radiation exposure is associated with damage to the gastrointestinal tract. Acute radiation causes direct damage to stem cells within the base of the crypts of Lieberkuhn, resulting in mitotic cessation and their death through apoptotic mechanisms (Potten 1997a, Potten 1997b). The recovery and / or long-term sequellae of this damage have been demonstrated to be related to both the GI microbiota and the innate immune repair response (Crawford 2005; Garg, 2010).
  • IDRs can reduce the peak intensity and duration of mucositis yielding ⁇ 50% reduction in the duration of severe mucositis ( Figure 1, Figure 2 , Figure 4 , Figure 5 , Figure 6 , Figure 7, Figure 8 , Figure 16, Figure 17).
  • IDRs are systemically administered and impact mucosal surfaces (e.g., oral mucosa, colon [ Figure 3 ]) as well as the skin and is effective in both systemic ( Figure 7, Figure 8 , Figure 9 and Figure 10 ) and local infections.
  • mucosal surfaces e.g., oral mucosa, colon [ Figure 3 ]
  • IDRs modulates the innate defense response to damage ( Figure 1 to Figure 8 , Figure 16, Figure 17).
  • RIVPA SEQ ID NO. 5
  • IDRs are efficacious in both immunocompetent and leukopenic animals - suggesting that the hematopoietic impacts which occur concomitantly with the GI component of ARS will not impair the efficacy of RIVPA (SEQ ID NO. 5).
  • RIVPA SEQ ID NO. 5
  • RIVPA SEQ ID NO. 5
  • RIVPA SEQ ID NO. 5
  • RIVPA SEQ ID NO. 5
  • RIVPA does not interfere with recovery from leukopenia ( Figure 15 ).
  • these studies strongly support the use of RIVPA (SEQ ID NO. 5) and other other IDRs treatment in response to acute radiation exposure to reduce acute mortality.

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